1. Field of the Invention
This invention relates to a water-insoluble pyrogen adsorbent which is effective in purging medicines, tonics, etc. of pyrogens, i.e., substances which, on entering living bodies in consequence of intravenous administration, e.g., by injection of medicines, tonics, and the like, produce fever.
2. Discussion of the Background
In the production of medicines and the like, for intravenous administration, the technique of purging medicines and the like, of pyrogens has a profound significance.
The term "pyrogens" as used herein refers to those which are classified under exotoxins which are excreted by Corynebacterium diphtheriae, Staphylococcus aureus, and the like, and endotoxins which are components of cellular walls of such gram-negative bacteria such as Escherichia coli, etc. Of these pyrogens, it is generally those of the latter class, i.e., the endotoxins occurring in the gram-negative bacteria that pose a problem. They have been identified as originating in lipid A, a glycolipid constituting itself the active center in the liposaccharide (LPS), i.e., the composite of lipid with polysaccharide.
It is thought that when a medicine entraining a pyrogen therewith happens to be intravenously administered, e.g., by injection, the pyrogen produces fever by acting on heat centers such as the hypothalamus. The fever may be very serious and at times may bring about death from shock. A manufacturer engaging in the production of a medicine for injection, therefore, is under the obligation to conduct a test with rabbits and confirm safety of the medicine by establishing that the medicine does not entrain any pyrogen with it.
In the existing methods available for the removal of such pyrogens from medicines, and the like, the method which effects the removal by adsorption with carbon powder or ion-exchange resin, the method which attains the removal by decomposing the pyrogen with an acid or an alkali, and the method which accomplishes the removal in a selective manner by the use of an ultra-membrane filter, for example, are renowned. A case of successful application of the composite having an imidazole-containing compound such as histamine or a nucleic acid base bonded to a dextran type gel carrier to the adsorptive removal of pyrogens has been reported in literature [Minobe et al: Journal of Chromatography, 262, 193-198 (1983)]. With respect to the conventional methods of the removal of pyrogens from medicines during their production, however, there remains many technical problems to be solved. The medicines themselves to be subjected to the treatment are not stable and the amounts of pyrogens to be removed are extremely small as compared with the amounts of medicines under treatment. With these and other drawbacks as contributory factors, the methods mentioned above have many technical problems yet to be solved for the purpose of effective application to the removal of pyrogens in the production of medicines on a commercial scale. The desirability of developing an effective and expeditious method capable of eliminating all of these problems has been finding growing recognition.
In the circumstances, it has been found that a novel pyrogen adsorbent characterized by using poly amino acid beads as a carrier and having an imidazole derivative deposited fast on the carrier excels in affinity for pyrogens and enjoys advantages in pyrogen adsorption treatment owing to the rigidity of the carrier (Japanese Patent Application Laid-Open (Kokai) HEI 1-127,039 (1989)). The preparation of the pyrogen adsorbent, however, necessitates a process of several steps of reactions and inevitably entails more or less operational intricacies. Moreover, the pyrogen adsorbent has a limited capacity for the incorporation of the imidazole derivative as a ligand and, consequently, a limited capacity for the adsorption of pyrogens.